Leonidas G. Roussias

Reproducibility of home, ambulatory, and clinic blood pressure: Implications for the design of trials for the assessment of antihypertensive drug efficacy

Abstract Background The aims of this study were to compare the reproducibility of blood pressure (BP) measured in the clinic (CBP), at home (HBP), and by ambulatory monitoring (ABP), and to assess its implications on the accuracy of antihypertensive drug trials. Methods A total of 133 untreated subjects with elevated CBP were assessed with repeated measurements of CBP (five visits within 3 months), HBP (6 workdays within 2 weeks), and ABP (twice, 2 weeks apart). The reproducibility of CBP (one visit), HBP (2 days), and ABP (24 h) was quantified using the SD of differences (SDD) between repeated measurements. The number of subjects required in a comparative trial of two drugs was calculated for each measurement method. Results We found that HBP provided the lowest SDD values (6.9/4.7 mm Hg, systolic/diastolic, compared with 8.3/5.6 for ABP and 11.0/6.6 for CBP). For a parallel trial aiming to detect a difference in the effect of two drugs of 10 mm Hg systolic BP, 51 subjects would be required when using CBP compared with 29 using ABP and 20 using HBP (73, 53 and 37 subjects, respectively, for the detection of a 5 mm Hg difference in diastolic BP). Conclusions The study shows that HBP seems to have superior reproducibility compared with both CBP and ABP. In addition, HBP can improve the accuracy of antihypertensive drug trials, thereby reducing the sample size required.

Parallel Morning and Evening Surge in Stroke Onset, Blood Pressure, and Physical Activity

Background and Purpose— A circadian variation with a morning peak on waking and arising is known to occur in both blood pressure (BP) and cardiovascular event onset. A second peak in BP has been described to occur after an afternoon sleep (siesta). This study was designed to investigate the hypothesis that the 2-peak diurnal variation of BP is dependent on physical activity and occurs in parallel with the diurnal variation of stroke onset. Methods— The diurnal variation of stroke onset was compared with the diurnal variation of BP, pulse rate (PR), and physical activity in 3 independent groups of Greek hypertensives 51 to 80 years of age (633 stroke patients, 379 subjects with 24-hour ambulatory BP monitoring, and 50 subjects with 24-hour physical activity monitoring through wrist devices). Results— The diurnal variation of stroke onset, BP, and PR all showed 1 morning and 1 evening peak with a decline in the afternoon and at night that occurred in parallel with the diurnal variation in physical activity (P <0.001 for differences among morning, afternoon, evening, and nighttime intervals in BP, PR, activity, and stroke). The afternoon decline in BP, PR, and activity was significant only in subjects with a siesta. Conclusions— The 2-peak diurnal variation in stroke onset occurred in parallel with the variation in BP, PR, and physical activity. These data support the hypothesis that an abrupt change in physical activity is not only a major determinant of the 2-peak diurnal variation of BP but also an important triggering factor for a cerebrovascular event.

Diagnosis of hypertension using home or ambulatory blood pressure monitoring: comparison with the conventional strategy based on repeated clinic blood pressure measurements.

Objective To investigate whether measurement of blood pressure at home (HBP) and by ambulatory monitoring (ABP) are reliable alternatives to the traditional strategy for the diagnosis of hypertension based on blood pressure measurement on repeated clinic visits (CBP). Design Comparison of the diagnosis of hypertension based on HBP (on six workdays) or ABP monitoring (two occasions) with that based on CBP (five visits within 3 months). Setting Outpatient hypertension clinic. Participants We enrolled 133 individuals with a diastolic CBP of 90–115 mmHg on the initial visit. Main outcome measures CBP, HBP and ABP values, and the diagnosis of hypertension. Results Hypertension was diagnosed in 70, 63 and 56% of individuals using the CBP, ABP and HBP methods respectively (P = 0.04). Agreement in the diagnosis of hypertension between all three methods was found in 59% of individuals. Disagreement between CBP and ABP was found in 27%, between CBP and HBP in 29% and between ABP and HBP in 26% of individuals. The sensitivity, specificity and positive and negative predictive values of ABP to diagnose hypertension correctly were 76, 67, 85 and 53% respectively; for HBP the respective values were 69, 77, 88 and 51%. The same parameters for HBP compared with ABP in the detection of white-coat hypertension were 61, 79, 48 and 86% respectively. Conclusions Indiscriminate use of HBP or ABP monitoring in the evaluation of all individuals with high blood pressure will probably result in confusion and therefore should be discouraged. However, in the detection of white-coat hypertension, HBP appears to be useful as a screening test, which, if positive, requires confirmation with ABP monitoring.

Additive hypotensive effect of angiotensin-converting enzyme inhibition and angiotensin-receptor antagonism in essential hypertension

The study was designed to assess the antihypertensive effect of combined angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) antagonism in patients with essential hypertension. Twenty patients with uncontrolled ambulatory diastolic blood pressure (BP) after 6 weeks of ACE inhibitor monotherapy (benazepril, 20 mg, o.d.) were randomized to receive double-blind valsartan, 80 mg, o.d. (AT1 antagonist) or matching placebo for 5 weeks while continuing to receive background benazepril. Then patients crossed over to the alternative regimen for a second 5-week period. The 24-h ambulatory BP was monitored on the final day of the benazepril monotherapy period and on the final day of each double-blind treatment period. Valsartan added to benazepril produced a significant antihypertensive effect with a benefit over placebo of 6.5 +/- 12.6/4.5 +/- 8.0 mm Hg (systolic/diastolic) for average awake ambulatory BP (p < 0.05), 7.1 +/- 9.4/5.6 +/- 6.5 mm Hg for asleep BP (p < 0.01), and 6.8 +/- 9.7/4.9 +/- 6.8 mm Hg for average 24-h ambulatory BP (p < 0.01). Pulse rate was unaffected. Plasma active renin was higher on the benazepril-valsartan combination compared with benazepril-placebo (p < 0.05). There was no change in routine biochemical variables when valsartan was added to benazepril. Six patients reported mild dizziness or fatigue (three also with placebo). These data suggest that in hypertensive patients uncontrolled with an ACE inhibitor, the addition of an AT1 antagonist provides a powerful and safe antihypertensive drug combination.

Diagnostic accuracy of home vs. ambulatory blood pressure monitoring in untreated and treated hypertension

Several studies with relatively small size and different design and end points have investigated the diagnostic ability of home blood pressure (HBP). This study investigated the usefulness of HBP compared with ambulatory monitoring (ABP) in diagnosing sustained hypertension, white coat phenomenon (WCP) and masked hypertension (MH) in a large sample of untreated and treated subjects using a blood pressure (BP) measurement protocol according to the current guidelines. A total of 613 subjects attending a hypertension clinic (mean age 53±12.4 (s.d.) years, men 57%, untreated 59%) had measurements of clinic BP (three visits, triplicate measurements per visit), HBP (6 days, duplicate morning and evening measurements) and awake ABP (20-min intervals) within 6 weeks. Sustained hypertension was diagnosed in 50% of the participants by ABP and HBP (agreement 89%, κ=0.79), WCP in 14 and 15%, respectively (agreement 89%, κ=0.56) and MH in 16% and 15% (agreement 88%, κ=0.52). Only 4% of the subjects (27/613) showed clinically significant diagnostic disagreement with BP deviation >5 mm Hg above the diagnostic threshold (for HBP or ABP). By taking ABP as reference, the sensitivity, specificity, positive and negative predictive value of HBP in detecting sustained hypertension were 90, 89, 89 and 90%, respectively, WCP 61, 94, 64 and 94% and MH 60, 93, 60 and 93%. Similar diagnostic agreement was found in untreated and treated subjects. HBP appears to be a reliable alternative to ABP in the diagnosis of hypertension and the detection of WCP and MH in both untreated and treated subjects.

Ambulatory arterial stiffness index, pulse pressure and pulse wave velocity in children and adolescents

Arterial stiffness, assessed by carotid–femoral pulse wave velocity (PWV) or indirectly by pulse pressure (PP) or ambulatory arterial stiffness index (AASI), is an independent predictor of cardiovascular disease in adults. However, in children limited evidence is available. This study investigated the usefulness of AASI and PP as indices of arterial stiffness in children and adolescents, by taking PWV as the reference method. Eighty-two children and adolescents (mean age 13.1±2.9 years) had 24-h ambulatory blood pressure (ABP) monitoring, PWV measurement and echocardiography. Compared with normotensives, subjects with hypertension (n=16) had higher 24-h ABP, 24-h PP and PWV, but not AASI. 24-h, PP was strongly correlated with age, weight, height, 24-h systolic ABP, PWV, left ventricular mass (LVM), LVM index, stroke volume and inversely with 24-h heart rate. AASI was also correlated with weight, height, systolic ABP and LVM, yet these associations were weaker than those of PP, and no significant correlations were found with PWV or LVM index. Moreover, closer agreement of PWV was observed with 24-h PP (71%, kappa 0.21) than with 24-h AASI (61%, kappa −0.06) in detecting subjects at the top quartile of the respective distributions. In children and adolescents, 24-h PP compared with AASI appears to be more closely associated with: (i) arterial stiffness assessed by PWV; (ii) target organ damage assessed by LVM index; and (iii) the presence of essential hypertension. These data suggest that the usefulness of AASI as an index of arterial stiffness in the pediatric population is questionable.

Clinic, home and ambulatory pulse pressure: comparison and reproducibility

OBJECTIVE: Recent evidence suggests that pulse pressure (PP) is an independent predictor of cardiovascular risk. The objective of this study was to compare mean values and reproducibility of PP obtained in the clinic (CPP), at home (HPP) and with ambulatory monitoring (APP) and to evaluate potential implications for trials aiming to assess drug effects on PP. METHODS: A total of 393 hypertensive subjects [mean age 51.5 +/- 11.5 (SD) years, 59% men, 35% treated] measured CPP (two visits), HPP (6 days) and APP (24 h). The reproducibility of PP was assessed using the SD of differences (SDD) between measurements in 133 untreated subjects who had repeated CPP (five visits), HPP (6 days) and APP measurements (two occasions). RESULTS: There was no difference between mean CPP (51.0 +/- 13.3 mmHg) and HPP (50.2 +/- 11.0) whereas APP (48.8 +/- 8.4) was lower than both CPP [mean difference 2.3 +/- 10.3 mmHg; 95% confidence interval (CI), 1.2, 3.3; P < 0.01] and HPP (1.5 +/- 7.8; 95% CI, 0.7, 2.3; P < 0.01). The SDD between repeated measurements was about 10 mmHg for CPP (one visit), 5.2 mmHg for HPP (2 days) and 4 mmHg for APP (24-h). For a parallel comparative trial aiming to detect a difference of 3 mmHg PP in the effect of two drugs, 415 subjects would be required when using CPP, compared to 127 using HPP and 63 using APP. CONCLUSIONS: These data suggest that although differences among mean values of CPP, HPP and APP are small, differences in their reproducibility are important and should be taken into account in the design of trials assessing drug effects on PP.

Morning Blood Pressure Surge: The Reliability of Different Definitions

Preliminary evidence suggests that the morning surge (MS) in blood pressure (BP) is an independent predictor of cerebrovascular disease. However, the optimal definition of MS is uncertain. To compare the reproducibility of several MS definitions used in the literature, 132 untreated hypertensives were assessed with ambulatory BP monitoring twice, 2 weeks apart. Five MS definitions were compared. MS-1: the average BP of the first hour after rising minus the average BP of the first hour before rising; MS-2: BP 2 h after rising minus that of 2 h before rising; MS-3: BP 3 h after rising minus that of 3 h before rising; MS-4: BP 2 h after rising minus the average BP during sleep; MS-5: BP 2 h after rising minus the average BP of 3 consecutive readings, centered on the lowest reading during sleep. The reproducibility of each MS definition was assessed using the concordance correlation coefficient (CCC), the standard deviation of differences (SDD) and the coefficient of variation (CV) between repeated MS assessments, and the agreement in detecting “surgers,” defined as subjects at the top quartile (Q4) of the MS distribution. CCCs were 0.20/0.30, 0.43/0.45, 0.53/0.51, 0.51/0.47, and 0.46/0.48 (systolic/diastolic) for MS-1 to MS-5 respectively; SDDs were 14.3/11.4, 12.1/9.9, 11.2/9.5, 10.3/8.2, and 11.9/9.8, respectively; CVs were 0.49/0.57, 0.44/0.39, 0.37/0.35, 0.36/0.31, and 0.27/0.24, respectively; and the agreement in detecting “surgers” was 69%/70%, 71%/76%, 75%/75%, 81%/ 83%, and 74%/75%, with k of 0.18/0.20, 0.23/0.36, 0.33/0.33, 0.49/0.53 and 0.29/0.31, respectively. There are important differences in the reproducibility of MS calculated by different methods. MS4 appears to provide the most reproducible definition of MS.

Ambulatory Arterial Stiffness Index: Reproducibility of Different Definitions

BACKGROUND Ambulatory arterial stiffness index (AASI) has been proposed as a marker of arterial stiffness, which predicts cardiovascular mortality. This study compared the reproducibility of 24-h, daytime, night time, and symmetrical AASI. METHODS A total of 126 untreated hypertensives (mean age 48.2 +/- 10.7 (s.d.) years, 70 men) underwent 24-h ambulatory blood pressure (ABP) monitoring twice 2-4 weeks apart. The reproducibility of AASI was assessed using the following criteria: (i) repeatability coefficient (RC = 2 x s.d. of differences); (ii) RC expressed as a percentage of close to maximal variation (pMV = RC/(4 x s.d. of the mean of paired recordings)); (iii) coefficient of variation (CV); (iv) concordance correlation coefficient (CCC); (v) agreement (kappa) between the two AASI measurements to detect subjects at the top quartile of the respective AASI distributions. RESULTS There was no difference in average AASI values between the two assessments. For 24-h, daytime, night time, and symmetrical AASI, respectively, (i) RC values were 0.24, 0.38, 0.42, and 0.30; (ii) pMV 49.6, 68.8, 73.9, and 56; (iii) CV 40.3, 39.3, 62.9, and 116.3; (iv) CCC 0.60, 0.35, 0.28, and 0.52; (v) agreement 82.5% (kappa 0.54), 72.2% (0.28), 73% (0.22), and 81.7% (0.50). Differences in 24-h mean arterial ambulatory pressure (MAP) and in nocturnal MAP decline between the two assessments were significant determinants of the differences in 24-h and symmetrical AASI values. CONCLUSIONS Although no differences were found in average AASI values of the two ambulatory recordings, significant differences were observed in their reproducibility, with 24-h AASI being the most reproducible measure in terms of all the examined criteria.American Journal of Hypertension 2010; doi:10.1038/ajh.2009.217.

Tracking of blood pressure from childhood to adolescence in a Greek cohort

BACKGROUND Studies have reported tracking of blood pressure (BP) from childhood to adulthood but with inconsistent results mainly due to methodological and ethnic differences. We aimed to examine BP tracking during a 7-year period in a Greek cohort. METHODS This is a longitudinal school-based study conducted during 1990-96 in Athens, Greece. Children underwent BP and anthropometric measurements on two to three visits annually (averaged to annual values) for 7 years. RESULTS A total of 166 children with complete yearly follow-up data for the examined period were included (mean baseline age 9 ± 1.7 years, range: 5-12 years, 89 boys). At baseline, the prevalence of pre- and hypertension was 22.9 and 24.1% respectively and at the end of the follow-up 24.1% (P = NS vs. baseline) and 13.3% (P = 0.02 vs. baseline) respectively. Systolic/diastolic BP tracking correlation coefficients between 1990 and 1996 were 0.38 (P < 0.001)/0.20 (P = 0.06) for boys and 0.30 (P = 0.007)/0.22 (P = 0.06) for girls. Among children with baseline BP ≥90th centile (systolic and/or diastolic), 44% remained in the same BP range after 7 years. In stepwise multiple regression analysis, baseline systolic BP, male gender, baseline body mass index (BMI) and change in BMI from baseline to the end of the follow-up (ΔBMI) were significant predictors of systolic BP levels at the end of the follow-up. Baseline diastolic BP, baseline BMI and ΔBMI were significant predictors of diastolic BP at the end of the follow-up. CONCLUSIONS These data suggest that the risk of developing high BP during adolescence can be predicted by BP and BMI at childhood.